In postoperative pain management, health care professionals generally are required to administer opioids, which is a potent analgesic. Although opioids have proven pain management properties, they also have a significant number of potential side effects, including nausea, vomiting, constipation, pruritus, urinary retention, respiratory depression, and sedation. On the other hand non-steroidal, anti-inflammatory drugs (NSAIDs) provide anti-inflammatory and analgesic effects, but they are limited to oral or rectal administrations greatly limiting the use of NSAIDs under postoperative conditions. Currently, ketorolac tromethamine is only NSAID that can be administered intravenously or intramuscularly, but its chronic use is limited due to GI toxicity.
Diclofenac, chemical name o-(2,6-dichloroanilino)phenylacetic acid, is known as a potent analgesic and antirheumatic and is described, in U.S. Pat. No. 3,558,690. Diclofenac is sold commercially as immediate release, delayed release (enteric coated) and extended-release (sustained-release) dosage forms. Due to the relatively large “first-pass-effect” of the substance and for faster flooding it is desirable to use injection solutions, in which an amount of 75 mg should be used per injection. For intramuscular/intravenous injections, the volume is to be kept as low as possible.
Due to the relatively poor solubility of diclofenac in water an aqueous injection solution with a reasonable volume cannot be obtained. Further, diclofenac is relatively instable in solution.
Examples of Diclofenac injectable compositions known in the art are:
U.S. Pat. No. 4,593,044 to Merckle GmbH describes a ready-to-use injection solution with as high an active compound content as possible in a small volume. The solubilization of diclofenac is achieved by using lysinate salt form of diclofenac and solubilizers such as propylene glycol, glycerol or polyoxyalkylenes.
U.S. Pat. No. 5,283,067 to Ciba-Geigy Corporation describes a lyophilized formulation comprising micronized diclofenac sodium, which is meant for intramuscular injection. This lyophilized formulation, after being suspended in an aqueous liquid vehicle, is converted into a dosage form for parenteral administration.
U.S. Pat. No. 5,389,681 to Ciba-Geigy Corporation describes a sterilizable parenteral solution comprising a diclofenac salt and stabilizers, such as ethyl lactate combined with glutathione or N-acetylcysteine.
U.S. Pat. No. 7,422,028 to Ibsa Institut Biochemique S.A. discloses aqueous solution comprising a complex of diclofenac and hydroxypropyl-β-cyclodextrin in the molar ratio of 1:1 and 1:1.3. The composition further comprises polysorbate in lower concentration. See also U.S. Pat. Nos. 4,309,421, 4,711,906, and 5,693,337; and U.S. App. Nos. 2011/0200657, 2005/0058699, and 2013/0156853
Although several of above references disclose various diclofenac injectable compositions, there exists a long felt need to develop a stable composition that is ready-to-inject intramuscularly or intravenously and causes minimal irritation to the tissues at the site of the injection.
It has been challenging to design a stable diclofenac parenteral composition that can be readily administered (without dilution or forming suspension) to alleviate pain or inflammation, especially in unconscious/unresponsive patients. It has also been challenging to formulate a composition that minimizes GI ulceration or bleeding after surgery, and other concurrent damage to the GI membranes or layers.
The present inventors provided compositions meant for parenteral administration comprising diclofenac or its pharmaceutically acceptable salt to a subject that can be used in postoperative pain management, with minimal or no side-effects and which, in some embodiments, can meet one or more of these needs.